This proposal focuses on the earliest steps in tumorigenesis: the origin of DNA damage that underlies the chain of genetic events that ultimately results in colonic cancer. Much has been elucidate in the past decade regarding the specific genetic events that lead to colonic tumorigenesis. Fundamental to this process are mutations and deletions in key tumor suppressor genes and oncogenes. However, central to this is the process that produces the genetic alterations in the first place. Our objective is to establish the role of oxidative stress in this regard, using the human model of ulcerative colitis (UC)-associated colonic neoplasia. UC is a chronic and diffuse inflammatory disease of the colonic mucosa with an increased risk of colon cancer, and is uniquely suited for studying the role of oxidative stress in tumorigenesis. UC neoplasia is hypothesized to be associated with widespread oxidative DNA damage and mutation, but direct evidence linking the two processes in currently lacking. Microsatellite instability, a marker of genome wide mutations, is present in non-neoplastic mucosa of patients with UC and we hypothesize that the genetic damage may be caused by oxidative stress and remains phenotypically occult until one or more specific genetic events precipitate neoplastic progression. Using the UC model, and the extensive human tissue database we have already developed, we will determine whether oxidative DNA damage and mutagenesis play a primary role in UC tumorigenesis. The application of several novel oxidative DNA damage assays a new oxygen free radical mutation assay that we have developed will provide a unique opportunity to unravel this potentially critical aspect of colonic tumorigenesis. This basic knowledge will be directly translated to clinical issues by determining if quantitative measurement of oxidative DNA damage and mutation can be used as intermediate markers of colonic neoplastic progression to improve cancer surveillance. Further, we will perform a pilot randomized, double-blind, placebo controlled intervention trial using dietary supplements in UC patients at highest risk. By preventing or decreasing oxidative DNA damage and mutagenesis, it may be possible to circumvent tumorigenesis entirely.